Despite the enormous efforts and resources directed at finding a cure, cancer remains an elusive and deadly foe for mankind. The standard methods of treatment usually include chemotherapy, radiation treatment, and surgical removal or tumors and/or growths, or some combination thereof. These treatments, combined with an emphasis on preventative lifestyle modification, have afforded a measure of success in the battle against some cancers. However, cancer remains one of the leading causes of mortality, and cancers detected at matured stages are invariably fatal.
Numerous chemical agents have been devised for the treatment of cancer with varying degrees of efficacy. However, no single drug has one hundred percent effectiveness against different cancers, and negative side-effects ranging from minor to serious are always present.
Recently, there has been much research directed toward the use of camptothecin and its derivatives to fight cancer. Isolated in 1966 from the Chinese tree Camptotheca acuminata, camptothecin was found to have significant efficacy in animal tumor models. Upon advancement to human clinical studies, camptothecin was found to have mixed results in fighting tumor growth and possessed side effects ranging from vomiting and diarrhea to myelosuppression and hemorrhagic cystitis. The side effects were so severe that Phase II clinical trials were eventually discontinued in the United States.
It is believed that camptothecin has a unique mechanism of action, i.e., via topoisomerase I DNA damage by binding and stabilizing a covalent DNA-topoisomerase I complex in which one of the DNA strands is broken. See Slichenmyer et al., "The Current Status Of Camptothecin Analogues As Antitumor Agents," J. Nat'l. Cancer Inst. 85:2 (1993) and references cited therein!. Among the formidable challenges facing any effort to develop the potential anticancer properties of camptothecin into a useable treatment are clearly the problems of drug delivery and toxicity.
Drug delivery is complicated by the fact that camptothecin is water-insoluble in its unmodified state. To this end several derivatives of camptothecin have been developed in order to address those two problems. In 1991, Kingsbury et al. see "Synthesis Of Water-Soluble (Aminoalkyl)camptothecin Analogues: Inhibition Of Topoisomerase I And Antitumor Activity," J. Med. Chem. 34:98(1991)! described the synthesis of several water-soluble analogs of camptothecin, by introduction of aminoalkyl groups into the camptothecin ring system. One of these analogs in particular, (s)-9-dimethylaminomethyl-10-hydroxycamptothecin hydrochloride!, later referred to as topotecan or TPT, was found to have significant anti-tumor effects when tested against various carcinoma cells in an in vitro clongenic assay. In animal studies, TPT was found to be at least as good or better than camptothecin in its effectiveness against tumor growth for a variety of cancers.
In human clinical studies, TPT was found to be clearly more promising than camptothecin in its efficacy. However, the derivative still caused several significant side effects, including myelosuppression, neutropenia, and thrombocytopenia.
Sawada et al. see "Synthesis And Antitumor Activity Of 20(S)-Camptothecin Derivatives: Carbamate-Linked, Water Soluble Derivatives Of 7-Ethyl-10-hydroxycamptothecin," Chem. Pharm. Bull 39:1446 (1991)! prepared several derivatives of camptothecin by bonding the phenolic hydroxyl group of 7-ethyl-10-hydroxycamptothecin with diamines through a monocarbamate linkage. These diamine derivatives were made water-soluble by conversion to their hydrochloride salts. One derivative in particular, 7-ethyl-10-4-(piperidino)-1 -piperidino!carboxylcamptothecin hydrochloride ("CPT-11"), possessed significant in vivo preclinical activity; it exhibited negligible in vitro activity as shown by its inability to inhibit Topoisomerase I activity see Kingsbury et al. supra! and tumor cell growth see Kingsbury et al. supra and Kawato et al., "Intracellular Roles Of SN-38, A Metabolite Of The Camptothecin Derivative CPT-11, In The Antitumor Effect Of CPT-11," Cancer Res. 51:4187 (1991)!, due to the fact that CPT-11 must first be metabolized by the body into its bioreactive form SN-38; thus making CPT-11 a "pro-drug." In fact, the in vivo preclinical anti-cancer effects of CPT-11 were more significant and wider ranging than either camptothecin or any other analog synthesized to date.
However, the promising effects of CPT-11 were still accompanied by significant side effects when the studies progressed to human clinical trials. Although the broad range of side effects was not generally present for CPT-11, severe respiratory complications combined with constant diarrhea pose significant challenges for CPT-11 based chemotherapy. See Slichenmeyer et al. supra!.
Clearly, there remains a need for a powerful anti-cancer derivative of camptothecin which does not possess significant side effects in humans undergoing treatment with such derivatives.